tbuckley/cabot-search huggingface dataset:
Cross-protein transfer learning substantially improves disease variant prediction
Authors: Milind Jagota, Chengzhong Ye, Carlos Albors, Ruchir Rastogi, Antoine Koehl, Nilah Ioannidis, Yun S Song
Journal: Genome biology (2023)

Genetic variation in the human genome is a major determinant of individual disease risk, but the vast majority of missense variants have unknown etiological effects. Here, we present a robust learning framework for leveraging saturation mutagenesis experiments to construct accurate computational predictors of proteome-wide missense variant pathogenicity.We train cross-protein transfer (CPT) models using deep mutational scanning (DMS) data from only five proteins and achieve state-of-the-art performance on clinical variant interpretation for unseen proteins across the human proteome. We also improve predictive accuracy on DMS data from held-out proteins. High sensitivity is crucial for clinical applications and our model CPT-1 particularly excels in this regime. For instance, at 95% sensitivity of detecting human disease variants annotated in ClinVar, CPT-1 improves specificity to 68%, from 27% for ESM-1v and 55% for EVE. Furthermore, for genes not used to train REVEL, a supervised method widely used by clinicians, we show that CPT-1 compares favorably with REVEL. Our framework combines predictive features derived from general protein sequence models, vertebrate sequence alignments, and AlphaFold structures, and it is adaptable to the future inclusion of other sources of information. We find that vertebrate alignments, albeit rather shallow with only 100 genomes, provide a strong signal for variant pathogenicity prediction that is complementary to recent deep learning-based models trained on massive amounts of protein sequence data. We release predictions for all possible missense variants in 90% of human genes.Our results demonstrate the utility of mutational scanning data for learning properties of variants that transfer to unseen proteins.
Diesel Exhaust Exposure and Cause-Specific Mortality in the Diesel Exhaust in Miners Study II (DEMS II) Cohort
Authors: Stella Koutros, Barry Graubard, Bryan A. Bassig, Roel Vermeulen, Nathan Appel, Marianne Hyer, Patricia A. Stewart, Debra T. Silverman
Journal: Environmental Health Perspectives (2023)

Background: With the exception of lung cancer, the health effects associated with diesel exhaust for other cancers and nonmalignant health outcomes are not well understood. Objectives: We extended the mortality follow-up of the Diesel Exhaust in Miners Study, a cohort study of 12,315 workers, by 18 y (ending 31 December 2015), more than doubling the number of observed deaths to n=4,887, to evaluate associations between mortality and diesel exhaust exposure. Methods: Quantitative estimates of historical exposure to respirable elemental carbon (REC), a surrogate for diesel exhaust, were created for all jobs, by year and facility, using measurements collected from each mine, as well as historical measurements. Standardized mortality ratios (SMRs) and hazard ratios (HRs) were estimated for the entire cohort and by worker location (surface, underground). Results: We observed an excess of death for cancers of the lung, trachea, and bronchus (n=409; SMR=1.24; 95% CI: 1.13, 1.37). Among workers who ever worked underground, where the majority of diesel exposure occurred, excess deaths were evident for lung, trachea, and bronchus cancers (n=266; SMR=1.26; 95% CI: 1.11, 1.42). Several nonmalignant diseases were associated with excess mortality among workers ever-employed underground, including ischemic heart disease (SMR=1.08; 95% CI: 1.00, 1.16), cerebrovascular disease (SMR=1.22; 95% CI: 1.04, 1.43), and nonmalignant diseases of the respiratory system (SMR=1.13; 95% CI: 1.01, 1.26). Continuous 15-y lagged cumulative REC exposure <1,280 μg/m3-y was associated with increased lung cancer risk (HR=1.93; 95% CI: 1.24, 3.03), but the risk declined at the highest exposures (HR=1.29; 95% CI: 0.74, 2.26). We also observed a significant trend in non-Hodgkin lymphoma (NHL) risk with increasing 20-y lagged cumulative REC (HRTertile3 vs. Tertile1=3.12; 95% CI: 1.00, 9.79; p-trend=0.031). Discussion: Increased risks of lung cancer mortality observed in the original study were sustained. Observed associations between diesel exposure and risk of death from NHL and the excesses in deaths for diseases of the respiratory and cardiovascular system, including ischemic heart disease and cerebrovascular disease, warrant further study and provide evidence of the potential widespread public health impact of diesel exposure. https://doi.org/10.1289/EHP12840
Membrane-localized neoantigens predict the efficacy of cancer immunotherapy
Authors: Zoe Goldberger, Sylvie Hauert, Kevin Chang, Trevin Kurtanich, Aaron T. Alpar, Grégoire Repond, Yue Wang, Suzana Gomes, Raga Krishnakumar, Prabha Siddarth, Melody A. Swartz, Jeffrey A. Hubbell, Priscilla S. Briquez
Journal: Cell Reports Medicine (2023)

Immune checkpoint immunotherapy (ICI) can re-activate immune reactions against neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI, the influence of the subcellular localizations of the neoantigens remains unclear. Here, we demonstrate in both a mouse melanoma model and human clinical datasets of 1,722 ICI-treated patients that a high proportion of membrane-localized neoantigens, particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further show that combining membrane localization and TMB analyses can enhance the predictability of cancer patient response to ICI. Our results may have important implications for establishing future clinical guidelines to direct the choice of treatment toward ICI.
mRNA vaccination boosts S-specific T cell memory and promotes expansion of CD45RAint TEMRA-like CD8+ T cells in COVID-19 recovered individuals
Authors: Koshlan Mayer-Blackwell, Heeju Ryu, Amy S. Codd, K. Rachael Parks, Hugh R. MacMillan, Kristen W. Cohen, Terri L. Stewart, Aaron Seese, Maria P. Lemos, Stephen C. De Rosa, Julie L. Czartoski, Zoe Moodie, Long T. Nguyen, Donald J. McGuire, Rafi Ahmed, Andrew Fiore-Gartland, M. Juliana McElrath, Evan W. Newell
Journal: Cell Reports Medicine (2023)

SARS-CoV-2 infection and mRNA vaccination both elicit spike (S)-specific T cell responses. To analyze how T cell memory from prior infection influences T cell responses to vaccination, we evaluated functional T cell responses in naive and previously infected vaccine recipients. Pre-vaccine S-specific responses are predictive of subsequent CD8+ T cell vaccine-response magnitudes. Comparing baseline with post-vaccination TCRβ repertoires, we observed large clonotypic expansions correlated with the frequency of spike-specific T cells. Epitope mapping the largest CD8+ T cell responses confirms that an HLA-A∗03:01 epitope was highly immunodominant. Peptide-MHC tetramer staining together with mass cytometry and single-cell sequencing permit detailed phenotyping and clonotypic tracking of these S-specific CD8+ T cells. Our results demonstrate that infection-induced S-specific CD8+ T cell memory plays a significant role in shaping the magnitude and clonal composition of the circulating T cell repertoire after vaccination, with mRNA vaccination promoting CD8+ memory T cells to a TEMRA-like phenotype.
Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid
Authors: Christopher Douville, Samuel Curtis, Mahmoud Summers, Tej D. Azad, Jordina Rincon-Torroella, Yuxuan Wang, Austin Mattox, Bracha Avigdor, Jonathan Dudley, Joshua Materi, Divyaansh Raj, Sumil Nair, Debarati Bhanja, Kyle Tuohy, Lisa Dobbyn, Maria Popoli, Janine Ptak, Nadine Nehme, Natalie Silliman, Cherie Blair, Kathy Judge, Gary L. Gallia, Mari Groves, Christopher M. Jackson, Eric M. Jackson, John Laterra, Michael Lim, Debraj Mukherjee, Jon Weingart, Jarushka Naidoo, Carl Koschmann, Natalya Smith, Karisa C. Schreck, Carlos A. Pardo, Michael Glantz, Matthias Holdhoff, Kenneth W. Kinzler, Nickolas Papadopoulos, Bert Vogelstein, Chetan Bettegowda
Journal: Cell Reports Medicine (2023)

It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.
High-dimensional profiling of pediatric immune responses to solid organ transplantation
Authors: Mahil Rao, Meelad Amouzgar, James T. Harden, M. Gay Lapasaran, Amber Trickey, Brian Armstrong, Jonah Odim, Tracia Debnam, Carlos O. Esquivel, Sean C. Bendall, Olivia M. Martinez, Sheri M. Krams
Journal: Cell Reports Medicine (2023)

Solid organ transplant remains a life-saving therapy for children with end-stage heart, lung, liver, or kidney disease; however, ∼33% of allograft recipients experience acute rejection within the first year after transplant. Our ability to detect early rejection is hampered by an incomplete understanding of the immune changes associated with allograft health, particularly in the pediatric population. We performed detailed, multilineage, single-cell analysis of the peripheral blood immune composition in pediatric solid organ transplant recipients, with high-dimensional mass cytometry. Supervised and unsupervised analysis methods to study cell-type proportions indicate that the allograft type strongly influences the post-transplant immune profile. Further, when organ-specific differences are considered, graft health is associated with changes in the proportion of distinct T cell subpopulations. Together, these data form the basis for mechanistic studies into the pathobiology of rejection and allow for the development of new immunosuppressive agents with greater specificity.
The Diesel Exhaust in Miners Study (DEMS) II: Temporal Factors Related to Diesel Exhaust Exposure and Lung Cancer Mortality in the Nested Case–Control Study
Authors: Debra T. Silverman, Bryan A. Bassig, Jay Lubin, Barry Graubard, Aaron Blair, Roel Vermeulen, Michael Attfield, Nathan Appel, Nathaniel Rothman, Patricia Stewart, Stella Koutros
Journal: Environmental Health Perspectives (2023)

Background: The Diesel Exhaust in Miners Study (DEMS) was an important contributor to the International Agency for Research on Cancer reclassification of diesel exhaust as a Group I carcinogen and subsequent risk assessment. We extended the DEMS cohort follow-up by 18 y and the nested case–control study to include all newly identified lung cancer deaths and matched controls (DEMS II), nearly doubling the number of lung cancer deaths. Objective: Our purpose was to characterize the exposure–response relationship with a focus on the effects of timing of exposure and exposure cessation. Methods: We conducted a case–control study of lung cancer nested in a cohort of 12,315 workers in eight nonmetal mines (376 lung cancer deaths, 718 controls). Controls were selected from workers who were alive when the case died, individually matched on mine, sex, race/ethnicity, and birth year (within 5 y). Based on an extensive historical exposure assessment, we estimated respirable elemental carbon (REC), an index of diesel exposure, for each cohort member. Odds ratios (ORs) were estimated by conditional regression analyses controlling for smoking and other confounders. To evaluate time windows of exposure, we evaluated the joint OR patterns for cumulative REC within each of four preselected exposure time windows, <5, 5–9, 10–19, and ≥20 y prior to death/reference date, and we evaluated the interaction of cumulative exposure across time windows under additive and multiplicative forms for the joint association. Results: ORs increased with increasing 15-y lagged cumulative exposure, peaking with a tripling of risk for exposures of ∼950 to<1,700 μg/m3-y [OR=3.23; 95% confidence interval (CI): 1.47, 7.10], followed by a plateau/decline among the heavily exposed (OR=1.85; 95% CI: 0.85, 4.04). Patterns of risk by cumulative REC exposure varied across four exposure time windows (phomogeneity<0.001), with ORs increasing for exposures accrued primarily 10–19 y prior to death (ptrend<0.001). Results provided little support for a waning of risk among workers whose exposures ceased for ≥20 y. Conclusion: DEMS II findings provide insight into the exposure–response relationship between diesel exhaust and lung cancer mortality. The pronounced effect of exposures occurring in the window 10–19 y prior to death, the sustained risk 20 or more years after exposure ceases, and the plateau/decline in risk among the most heavily exposed provide direction for future research on the mechanism of diesel-induced carcinogenesis in addition to having important implications for the assessment of risk from diesel exhaust by regulatory agencies. https://doi.org/10.1289/EHP11980
Electro-metabolic coupling in multi-chambered vascularized human cardiac organoids
Authors: Mohammad Ghosheh, Avner Ehrlich, Konstantinos Ioannidis, Muneef Ayyash, Idit Goldfracht, Merav Cohen, Amit Fischer, Yoav Mintz, Lior Gepstein, Yaakov Nahmias
Journal: Nature Biomedical Engineering (2023)
Tissue perfusion pressure enables continuous hemodynamic evaluation and risk prediction in the intensive care unit
Authors: Anand Chandrasekhar, Raimon Padrós-Valls, Roger Pallarès-López, Eric Palanques-Tost, Nicholas Houstis, Thoralf M Sundt, Hae-Seung Lee, Charles G Sodini, Aaron D Aguirre
Journal: Nature Medicine (2023)
Generative appearance replay for continual unsupervised domain adaptation
Authors: Boqi Chen, Kevin Thandiackal, Pushpak Pati, Orcun Goksel
Journal: Medical Image Analysis (2023)

Deep learning models can achieve high accuracy when trained on large amounts of labeled data. However, real-world scenarios often involve several challenges: Training data may become available in installments, may originate from multiple different domains, and may not contain labels for training. Certain settings, for instance medical applications, often involve further restrictions that prohibit retention of previously seen data due to privacy regulations. In this work, to address such challenges, we study unsupervised segmentation in continual learning scenarios that involve domain shift. To that end, we introduce GarDA (Generative Appearance Replay for continual Domain Adaptation), a generative-replay based approach that can adapt a segmentation model sequentially to new domains with unlabeled data. In contrast to single-step unsupervised domain adaptation (UDA), continual adaptation to a sequence of domains enables leveraging and consolidation of information from multiple domains. Unlike previous approaches in incremental UDA, our method does not require access to previously seen data, making it applicable in many practical scenarios. We evaluate GarDA on three datasets with different organs and modalities, where it substantially outperforms existing techniques. Our code is available at: https://github.com/histocartography/generative-appearance-replay.
Modified red light 5-aminolevulinic acid photodynamic therapy versus low-dose isotretinoin therapy for moderate to severe acne vulgaris: A prospective, randomized, multicenter study
Authors: Linglin Zhang, Yutong Yang, Bo Wang, Yan Zhao, Peiru Wang, Jia Liu, Jiayi Yang, Yun Wu, Ting Lv, Ziyu Wei, Xiaojing Liu, Ruiping Wang, Harrison Wong, Qiang Ju, Lei Shi, Xiuli Wang
Journal: Journal of the American Academy of Dermatology (2023)
Bone-matrix mineralization dampens integrin-mediated mechanosignalling and metastatic progression in breast cancer
Authors: Siyoung Choi, Matthew A. Whitman, Adrian A. Shimpi, Nicole D. Sempertegui, Aaron E. Chiou, Joseph E. Druso, Akanksha Verma, Stephanie C. Lux, Zhu Cheng, Matthew Paszek, Olivier Elemento, Lara A. Estroff, Claudia Fischbach
Journal: Nature Biomedical Engineering (2023)
Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging
Authors: Daniel B Rosoff, Lucas A Mavromatis, Andrew S Bell, Josephin Wagner, Jeesun Jung, Riccardo E Marioni, George Davey Smith, Steve Horvath, Falk W Lohoff
Journal: Nature Aging (2023)

Abstract The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor (‘mvAge’). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1 . Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge ( P value = 8.41 × 10 −5 ). Similarly, genetically proxied thiazolidinediones ( P value = 3.50 × 10 −10 ), proprotein convertase subtilisin/kexin 9 inhibition ( P value = 1.62 × 10 −6 ), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.
Gut microbiota controls the development of chronic pancreatitis: A critical role of short-chain fatty acids-producing Gram-positive bacteria
Authors: Li-Long Pan, Zheng-Nan Ren, Jun Yang, Bin-Bin Li, Yi-Wen Huang, Dong-Xiao Song, Xuan Li, Jia-Jia Xu, Madhav Bhatia, Duo-Wu Zou, Chun-Hua Zhou, Jia Sun
Journal: Acta Pharmaceutica Sinica B (2023)

Chronic pancreatitis (CP) is a progressive and irreversible fibroinflammatory disorder, accompanied by pancreatic exocrine insufficiency and dysregulated gut microbiota. Recently, accumulating evidence has supported a correlation between gut dysbiosis and CP development. However, whether gut microbiota dysbiosis contributes to CP pathogenesis remains unclear. Herein, an experimental CP was induced by repeated high-dose caerulein injections. The broad-spectrum antibiotics (ABX) and ABX targeting Gram-positive (G+) or Gram-negative bacteria (G-) were applied to explore the specific roles of these bacteria. Gut dysbiosis was observed in both mice and in CP patients, which was accompanied by a sharply reduced abundance for short-chain fatty acids (SCFAs)-producers, especially G+ bacteria. Broad-spectrum ABX exacerbated the severity of CP, as evidenced by aggravated pancreatic fibrosis and gut dysbiosis, especially the depletion of SCFAs-producing G+ bacteria. Additionally, depletion of SCFAs-producing G+ bacteria rather than G- bacteria intensified CP progression independent of TLR4, which was attenuated by supplementation with exogenous SCFAs. Finally, SCFAs modulated pancreatic fibrosis through inhibition of macrophage infiltration and M2 phenotype switching. The study supports a critical role for SCFAs-producing G+ bacteria in CP. Therefore, modulation of dietary-derived SCFAs or G+ SCFAs-producing bacteria may be considered a novel interventive approach for the management of CP.
Sensing the DNA-mismatch tolerance of catalytically inactive Cas9 via barcoded DNA nanostructures in solid-state nanopores
Authors: Sarah E Sandler, Nicole E Weckman, Sarah Yorke, Akashaditya Das, Kaikai Chen, Richard Gutierrez, Ulrich F Keyser
Journal: Nature Biomedical Engineering (2023)

Abstract Single-molecule quantification of the strength and sequence specificity of interactions between proteins and nucleic acids would facilitate the probing of protein–DNA binding. Here we show that binding events between the catalytically inactive Cas9 ribonucleoprotein and any pre-defined short sequence of double-stranded DNA can be identified by sensing changes in ionic current as suitably designed barcoded linear DNA nanostructures with Cas9-binding double-stranded DNA overhangs translocate through solid-state nanopores. We designed barcoded DNA nanostructures to study the relationships between DNA sequence and the DNA-binding specificity, DNA-binding efficiency and DNA-mismatch tolerance of Cas9 at the single-nucleotide level. Nanopore-based sensing of DNA-barcoded nanostructures may help to improve the design of efficient and specific ribonucleoproteins for biomedical applications, and could be developed into sensitive protein-sensing assays.
A commentary on ‘Management of leaks following one-anastomosis gastric bypass: an updated systematic review and meta-analysis of 44 318 patients’
Authors: Chao-Ming Hung, Chi-Ming Tai, Chong-Chi Chiu
Journal: International Journal of Surgery (2023)

aDepartment of General Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan bSchool of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan cDivision of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan dSchool of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan eDepartment of Medical Education and Research, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: No.21, Yi-Da Road, Jiao-Su Village, Yan-Chao District, Kaohsiung, 824, Taiwan, Tel: 886-76150022, Fax: 886-76150940. E-mail address: [email protected] (C-C. Chiu). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
A commentary on ‘Learning curves in laparoscopic distal pancreatectomy: a different experience for each generation (Int J Surg. 2023;109(6):1648–55)’
Authors: Min Wu, Yonghua Lin, Jianfeng Wei
Journal: International Journal of Surgery (2023)

Hepatobiliary Surgery Department, Second Affiliated Hospital of Fujian Medical University, No.950 Donghai Street, Quanzhou 362000, Fujian, China Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Hepatobiliary Surgery Department, Second Affiliated Hospital of Fujian Medical University, No.950 Donghai Street, Quanzhou 362000, Fujian, China. E-mail address: [email protected] (J. Wei) This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/